Primary biliary cirrhosis and primary sclerosing cholangitis are irreversible liver diseases of unknown etiology with no available treatment or preventive therapy, and only liver transplantation can prolong life of patients with disease progression. The hallmark of these diseases is fibrotic accumulation around hepatic bile ducts that normally drain bile from liver to intestine. This periductular fibrosis causes bile duct compression and cholestasis. Biliary epithelial cells (BEC) line each of these bile ducts and are in direct contact with the accumulating fibrotic tissue. Our goal is to use these BEC as a target cell type for gene therapy intervention aimed at halting disease progression. The advantages of this approach in terms of gene delivery potential are: 1) BECs are always in a direct contact with compressing fibrotic tissue; and 2) BECs are readily accessible using a endoscopic procedure commonly used in the clinic. A mouse model of peribiliary fibrosis/cirrhosis induced by common bile duct ligation has been developed and will be ideal for these studies. We will use this mouse model to deliver gene complexes to BEC's via a catheter. The overall goal is to identify non-viral transfection vectors and/or methodologies that deliver genes to the BEC with high efficiency. Phase II of this research will incorporate the most efficient gene delivery complexes to identify specific genes that are effective in blocking peribiliary cirrhosis development. PROPOSED COMMERCIAL APPLICATIONS: Primary biliary cirrhosis and primary sclerosing cholangitis are irreversible liver diseases in which liver transplantation is the only viable treatment. However, this treatment is limited by shortage of donor livers and extremely high cost. This grant is ultimately aimed at identifying alternative gene therapy treatments for these diseases. The phase I grant will determine the feasibility of delivering genes into the disease associated cells using non-viral vectors.